tbuckley/cabot-search huggingface dataset:
Abstract 6690: Monitoring response and resistance to EGFR inhibition with circulating tumor DNA in a non-small cell lung cancer patient-derived xenograft
Authors: Long H. Do, Raffaella Pippa, Warren Andrews, Yuan Chien, Jantzen Sperry, Jonathan Nakashima
Journal: Cancer Research (2023)

Abstract Circulating tumor DNA (ctDNA) has been shown as a clinically relevant biomarker for non-invasive monitoring of therapy response, disease burden and disease progression in cancer patients. Patient-derived xenografts (PDX) are essential translational models used for evaluating therapeutic response and identifying novel biomarkers, but analysis of ctDNA in these models remains understudied. Here, we report the use of ctDNA for the monitoring of therapeutic response and secondary resistance of a Non-Small Cell Lung Cancer PDX treated with EGFR inhibitors. We demonstrate measurable ctDNA changes correlate with disease burden and therapeutic response. Altogether, the isolation of ctDNA from PDX models is a robust methodology for interrogating therapeutic efficacy, response, and resistance in a preclinical setting that can be translated as a viable biomarker for non-invasive monitoring in patients. Citation Format: Long H. Do, Raffaella Pippa, Warren Andrews, Yuan Chien, Jantzen Sperry, Jonathan Nakashima. Monitoring response and resistance to EGFR inhibition with circulating tumor DNA in a non-small cell lung cancer patient-derived xenograft. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6690.
Abstract 4740: Molecular effects of histone deacetylase inhibitor Quisinostat on diffuse midline glioma of the pons
Authors: Danyelle Paine, Nanyun Tang, Yue Hao, Matt Biery, Carrie Meyers, Alyssa Noll, Nicholas Vitanza, Michael Berens
Journal: Cancer Research (2023)

Abstract Diffuse Midline Glioma of the pons (DMG) is a lethal, aggressive heterogeneous brain stem tumor. Median overall survival is less than a year, with radiation as the only standard treatment. Recently, mutations in DMGs have arisen as potential therapeutic targets, specifically a mutation in one of the histone H3 genes, resulting in methionine substituted for lysine at site 27 (H3K27M). H3K27M induces a marked reduction in global acetylation of histone tails, altering chromatin structure and causing aberrant gene expression. Histone deacetylase inhibitors, HDACis, are epigenetic drugs that show anticancer activity. In our studies, Quisinostat (Quis) is used to preserve histone acetylation. Using two H3K27M-DMG treatment-naive preclinical models (PBT22 and PBT29) we detected a 100-fold differential response to the histone deacetylase inhibitor, Quisinostat. PBT-22 harbors mutations in H3F3A, TP53, and ASXL2, while PBT-29 has mutations in H3F3A, TP53, PIK3CA and FGFR1. Following Quis treatment (48 hrs) in both preclinical models, total H3K27ac protein abundance increased 3-fold, suggesting HDACi stabilizes or impedes turnover of K27 acetylated H3 histone. We are pursuing studies to test whether sensitivity to HDACi in DMGs is determined by a shift in relative or total abundance of respective H3wt- and H3K27M- histones. We posit that changes in H3K27ac manifest as shifts in nucleosome integration with genes responsible for cell survival/death. This project will profile differentially expressed genes (DEGs) from Quis-treated PBT22 and PBT29. Additionally, total and relative abundance of H3 proteins (wt and mt, me, me2, me3, and ac) from treated cells will be determined. Gene ontology analysis will focus on pathways accounting for chromatin remodeling, cell death, and growth arrest. RNA (qRT-PCR) and proteins (western blot) from analytes from a larger panel of DMG cell lines and neural stem cells treated with Quis will be used to validate the findings. Overall, the data depicts DMG preclinical models with large differential sensitivity to Quis, which may be partially due to different oncoprints between the models. The markedly different sensitivity of these models enables mechanistic study of the consequences of elevated abundance of histone 3 acetylation. The long term goal is to discover a molecular profile of DMGs indicative of the vulnerability to HDACi. Citation Format: Danyelle Paine, Nanyun Tang, Yue Hao, Matt Biery, Carrie Meyers, Alyssa Noll, Nicholas Vitanza, Michael Berens. Molecular effects of histone deacetylase inhibitor Quisinostat on diffuse midline glioma of the pons. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4740.
Abstract 4943: SP-1-39 as a novel tubulin inhibitor overcomes taxane resistance in castration-resistant prostate cancer model
Authors: Rui Wang, Kelli L. Hartman, Satyanarayana Pochampally, Duane D. Miller, Wei Li
Journal: Cancer Research (2023)

Abstract Colchicine binding site inhibitors have proven to have potent anti-cancer efficacy in many cancer types. Inhibition of tubulin polymerization, a popular mechanism of action for anti-cancer activities, will be activated once the inhibitor interacts with the colchicine binding site. We have previously developed and reported a potent tubulin inhibitor (SB-216). One of its derivatives, the compound SP-1-39, a pyrimidine dihydroquinoxalinone derivative, has been recently designed to further improve the potency and therapeutic properties. Here, we examined the impact of SP-1-39 on preclinical prostate cancer models in vitro and in vivo. EBI competition assay confirmed that SP-1-39 binds to colchicine-binding site and inhibits the formation of EBI:β-tubulin adduct. The anti-proliferation abilities of SP-1-39 was tested against melanoma, breast cancer, pancreatic cancer, prostate cancer, and paclitaxel-resistant prostate cancer cell lines by MTS assay, and defined IC50 values of 0.2-4 nmol/L. Other in vitro results showed SP-1-39 disrupted microtubule network, induced cell cycle arrest at G2/M phase, and caused apoptosis in paclitaxel-resistant human prostate cancer cells (PC-3/TxR). For in vivo study, 2.5mg/kg SP-1-39 significantly attenuated tumor growth in PC-3/TxR xenograft mouse model, inhibited angiogenesis, and overcame taxane resistance. Our findings demonstrate the preclinical therapeutic efficacy and safety of SP-1-39, and provide support for further exploration of novel tubulin inhibitors as anti-cancer agent for cancer therapy. Citation Format: Rui Wang, Kelli L. Hartman, Satyanarayana Pochampally, Duane D. Miller, Wei Li. SP-1-39 as a novel tubulin inhibitor overcomes taxane resistance in castration-resistant prostate cancer model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4943.
Abstract 151: Optimization of screening conditions using patient-derived organoids for diagnostic purposes
Authors: Carla S. Verissimo, Lidwien Smabers, Emerens Wensink, Esmee Koedoot, Katerina-Chara Pitsa, Mayke Doorn, Inez van Weersch, Hamdy Warda, Celia Higuera Barón, Gerben ten Hag, Robert G. Vries, Jeanine Roodhart, Sylvia F. Boj
Journal: Cancer Research (2023)

Abstract Patient-derived organoids (PDOs) are increasingly adopted in preclinical research. PDOs, or HUB Organoids®, are directly established from patient tissue, faithfully recapitulate patient disease, and effectively bridge the gap between the lab and the clinic, bringing a “patient in the lab®”. PDOs can also revolutionize clinical research because they can predict patient response to standard-of-care (SoC) compounds. However, there is an urgent need to refine the assay conditions to evaluate the activity of SoC drugs with different mechanisms of action (topoisomerase inhibitors, alkylating agents, targeted agents) and various types of molecules (small molecules, antibodies) and achieve optimal results from the PDO-based assay. Specifically, for metastatic colorectal cancer (mCRC), we have optimized the media composition required for drug screening assays to test response to SoC, such as oxaliplatin and panitumumab. Our results indicate that optimal media conditions are essential to observe an in vitro drug response in PDOs similar to the patient response in the clinic. In addition, an image-based readout was developed that enables precise quantification of organoid numbers ensuring high assay quality. Optimizing screening conditions to evaluate SoC compounds in PDOs is a required step to accelerate the implementation of the HUB Organoid Technology as a diagnostic platform to accurately predict treatment response and improve clinical outcomes for cancer patients. Citation Format: Carla S. Verissimo, Lidwien Smabers, Emerens Wensink, Esmee Koedoot, Katerina-Chara Pitsa, Mayke Doorn, Inez van Weersch, Hamdy Warda, Celia Higuera Barón, Gerben ten Hag, Robert G. Vries, Jeanine Roodhart, Sylvia F. Boj. Optimization of screening conditions using patient-derived organoids for diagnostic purposes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 151.
Abstract 4797: β3-AR blockade induces differentiation of malignant leukemia T cells in mature T lymphocytes
Authors: Francesco Carrozzo, Gennaro Bruno, Claudia Masi, Alessia Boaretto, Claudio Favre, Maura Calvani
Journal: Cancer Research (2023)

Abstract Acute lymphoblastic leukemia (ALL) is a genetically heterogeneous cancer that arises from diverse genetic alterations during early lymphocyte development. About 10-15% of T-cell acute lymphoblastic leukemia (T-ALL) cases occur in childhood; despite having an event-free survival (EFS) rate of 85%, relapse is the main problem of this type of cancer. Mitochondria metabolic reprogramming plays a crucial role in the development of lymphocytes both in physiological and pathological processes such as differentiation and neoplastic transformation respectively. Mitochondria are the main actors of cellular homeostasis. They use glycolysis products exploiting them in the Krebs cycle and in oxidative phosphorylation to produce energy and plays key roles in reactive oxygen species (ROS) generation, Ca2+ signaling, cell death induction, and cellular differentiation. In particular, the increase of ROS is important to reduce tumor cell viability and at the same time is involved in induction of hematopoiesis. β3-adrenoreceptors (β3-Ars) is a class of receptors associated with pro-tumoral signaling in different tumors. In this study, we first have observed the expression of β3-Ars in leukemia T cells and then we studied how the modulation of this receptors affected tumor-related pathways. The treatment with an antagonist of β3-Ars (SR59230A) induced an increase of ROS leading to lymphoblastic cells differentiation, decrease of proliferation and enhanced induction of apoptosis signaling. Overall, these results suggest that β3-Ars could be a possible target for treatment of T-ALL. Citation Format: Francesco Carrozzo, Gennaro Bruno, Claudia Masi, Alessia Boaretto, Claudio Favre, Maura Calvani. β3-AR blockade induces differentiation of malignant leukemia T cells in mature T lymphocytes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4797.
Abstract 2224: Applying optical genome mapping to detect genomic biomarkers and use for residual disease monitoring in hematologic malignancies
Authors: Alex Chitsazan, Andy Pang, Alex Hastie
Journal: Cancer Research (2023)

Abstract Disease monitoring is important to detect cancer relapse, often as a result of a treatment-surviving cancer cell population. Detection of relapse is critical to determine the intensity and length of treatments and to predict the outcome of those treatments. Currently, karyotyping, fluorescent in situ hybridization (FISH), flow cytometry, PCR, and next-generation sequencing (NGS) are often used for this application. PCR is sensitive and highly effective, but as a targeted approach, it requires the identification of an appropriate biomarker. Karyotyping and FISH are used to follow structural variants, especially those detected at diagnosis and known to be drivers of carcinogenesis; however, karyotype has low sensitivity (~5-10% variant allele frequency (VAF)) and FISH is only targeted.We describe a novel workflow to find structural variants (SVs) using optical genome mapping (OGM) and to use those SVs as biomarkers for disease monitoring assessment. The initial SV profile from a cancer sample can be obtained by running the standard somatic workflow for OGM: 1.5 Tbp of high molecular genomic DNA is collected (without any amplification/selection), and molecules that can capture SV breakpoints are locally assembled into genome maps. These locally assembled genome maps are used to make high-confidence SV calls at least 5 kbp in size. Then, presumptive somatic variants are revealed by further comparison against an OGM control sample SV database (included in Bionano Access/Solve software). Subsequently, to detect residual cancer cells post-treatment, an ultra-deep coverage of approximately 5 Tbp of DNA can be collected, and these molecules are directly aligned to the genome maps in the initial cancer sample. This direct alignment approach is fast and sensitive in identifying remnants of pretreatment originator cells. We are currently applying this workflow to recover known leukemia-associated inter-chromosomal translocations, and our preliminary results indicate a sensitivity of detecting calls at a minimum of 0.5% VAF. Continual investigation on limit of detection is ongoing, but with the improvement on throughput and algorithms, we envision that this workflow to be essential in discovering low level clonal cancerous DNA. Citation Format: Alex Chitsazan, Andy Pang, Alex Hastie. Applying optical genome mapping to detect genomic biomarkers and use for residual disease monitoring in hematologic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2224.
Abstract 5475: Improved prediction of immunotherapy responses by constitutive neoantigen load and LINE-1 methylation
Authors: Hyoeun Bang, Jeong Yeon Kim, Cheolyong Joe, Kyeonghui Kim, Younghak Bang, Hyemin Kim, Honghi Cha, Eunjoo Oh, Naeun Lee, Inkyung Shin, Seung-Jae Noh, Dae-Yeon Cho, Se-Hoon Lee, Jung Kyoon Choi
Journal: Cancer Research (2023)

Abstract Previous biomarkers such as PD-L1 expression, tumor mutation burden (TMB), and neoantigen load have limited accuracy in predicting responses to immune checkpoint inhibitor (ICI) therapy. In this work, we propose an improved predictor of ICI responses on the basis of our previous findings on the role of neoantigen functionality and genomic hypomethylation in tumor immunity. Specifically, we developed a metric of constitutive neoantigen load given the association of constitutive neoantigens derived from genes indispensable for cancer growth with favorable clinical responses to ICI (Clin. Transl. Med. 12:e714). A panel that captures somatic mutations on the 300 most essential genes identified by genome-wide screening in ~1,800 pan-cancer cell lines was used. Our DeepNeo algorithm (Nat. Commun. 11:951; Nat. Genet. 2023) was employed to identify T cell-reactive neoantigens from somatic mutations binding patient-matched HLA proteins. Also, considering the role of genomic hypomethylation in inducing resistance of tumors to ICI therapy (Nat. Commun. 10:4278), we developed an assay that estimates genomic hypomethylation by targeted sequencing of LINE-1 elements. Constitutive neoantigen load and LINE-1 methylation status were evaluated in our cohort consisting of 335 lung cancer patients treated with ICIs. As a result, constitutive neoantigen load (HR=0.671; p-value=3.13E-03) and LINE-1 methylation (HR=0.597; p-value=0.012) outperformed PD-L1 (HR=0.74; p-value=0.199), TMB (HR=0.917; p-value=0.511), and the combination of PD-L1 and TMB (HR=0.707; p-value=0.218). The combination of constitutive neoantigen load and LINE-1 methylation (HR=0.245; p-value=1.11E-05) showed even better predictive power. In conclusion, our approach can be used as new companion diagnostics for ICI-based immune-oncology. Citation Format: Hyoeun Bang, Jeong Yeon Kim, Cheolyong Joe, Kyeonghui Kim, Younghak Bang, Hyemin Kim, Honghi Cha, Eunjoo Oh, Naeun Lee, Inkyung Shin, Seung-Jae Noh, Dae-Yeon Cho, Se-Hoon Lee, Jung Kyoon Choi. Improved prediction of immunotherapy responses by constitutive neoantigen load and LINE-1 methylation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5475.
Abstract 593: Bispecific antibody against TIGIT and PVRIG enhances antitumor immunity
Authors: Jiabei Liang, Xiao Gao, Cong Zhang, Hui Zhao, Hao Peng, Feng Hao, Jinying Ning, Guojin Wu
Journal: Cancer Research (2023)

Abstract T cell immunoreceptor with Ig and ITIM domains (TIGIT) and poliovirus receptor-related immunoglobulin domain-containing protein (PVRIG) are two immune checkpoint receptors. They compete with CD226 for binding to CD155 or CD112 and suppress the activity of NK cells and T cells. Here we developed a bispecific antibody KA-1874 targeting TIGIT with an anti-PVRIG scFv fused to the C-terminus. KA-1874 is a fully human IgG4 with high binding affinity to TIGIT (KD=0.08nM) and PVRIG (KD=0.17nM). KA-1874 blocks both bindings of PVRIG-mFc to PVRL2 and TIGIT-mFc to CD155. In cell-based luciferase reporter assays, KA-1874 blocks PVRIG and TIGIT-mediated inhibitory signaling and enhances CD3 signaling with EC50 of 1.1nM and 1.4nM respectively, while COM701 against PVRIG and EOS488 against TIGIT both with EC50 above 2nM. In a CMV recall assay, PBMC increases INF-γ secretion when cultured with KA-1874, suggesting KA-1874 enhances primary T cell function. Immunodeficient mice humanized with PBMC are transplanted with A374 tumor cells. Co-injection of KA-1874 and pembrolizumab, which against PD-1, suppress established tumor growth. In comparison, KA-1874 or pembrolizumab alone fails to inhibit tumor growth. The above results indicate KA-1874 is an excellent candidate therapeutical antibody for cancer immunotherapy. Citation Format: Jiabei Liang, Xiao Gao, Cong Zhang, Hui Zhao, Hao Peng, Feng Hao, Jinying Ning, Guojin Wu. Bispecific antibody against TIGIT and PVRIG enhances antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 593.
Abstract 995: Evaluation of plasma cytokines and chemokines as potential biomarkers for colorectal cancer detection
Authors: Elba V. Caraballo, Hilmaris Centeno-Girona, Yilda Macias, Madeline M. Mártir Ocasio, Marcia R. Cruz-Correa
Journal: Cancer Research (2023)

Abstract Despite evidence suggesting that current Colorectal Cancer (CRC) screening strategies reduce mortality rates, screening compliance is suboptimal; for this, our study aimed to evaluate the discriminatory potential of plasma cytokine and chemokine levels for CRC detection in plasma samples in a Hispanic subpopulation. Using a retrospective case-control study design, we evaluated plasma samples in 20 CRC cases and 20 age-gender matched controls from the Puerto Rico Familial Colorectal Cancer Registry (PURIFICAR). BD CBA Human Th1/Th2/Th17 Cytokine and Human Chemokine kits were used to prepare plasma samples for flow cytometric analysis (Becton-Dickinson &amp; Co). Mann-Whitney-U test was used to detect differences between biomarkers and case-control groups. Measures of diagnostic accuracy were estimated for comparisons according to CRC disease stage. We compared multivariable models to determine the best CRC case-classifier. The median levels of six of the cytokines evaluated (IL-2, IL-4, IL-6, IL-10, TNF, and IL-17A) and one chemokine (CXCL10-/IP-10) significantly differed between cases and controls (P&amp;lt;0.05). ROC plots and logistic regression analysis showed that these seven biomarkers displayed good to excellent accuracy (AUC: 0.6-0.9). Multivariate analysis showed that the best-case classifying model included the seven statistically significant markers. Our findings suggest that discriminatory biomarker levels between CRC cases and controls observed show their great potential as targets in novel blood-based screening tests for CRC. The development of a non-invasive CRC screening test will provide an alternative to increasing adherence, early detection, survivorship, and a tool for a population-based prevention strategy approach. Citation Format: Elba V. Caraballo, Hilmaris Centeno-Girona, Yilda Macias, Madeline M. Mártir Ocasio, Marcia R. Cruz-Correa. Evaluation of plasma cytokines and chemokines as potential biomarkers for colorectal cancer detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 995.
Abstract 4972: Anti-tumor activity of Helicon inhibitors of Β-catenin-TCF interaction in patient-derived xenograft models
Authors: YaGuang Si, Minjung Choi, Xinwei Han, Brian White, Ziyang Wu, Erica Visness, Pieter Beerepoot, Elizabeth Jaensch, Jessica Ramirez, Charles Ponthier, Xiaogang Han, Paula Ortet, Peicheng Du, Sorabh Agarwal, Mirek Lech, Aaron Fulgham, Sarah Cappucci, Zhi Li, John McGee, Lihua Yu, Martin Tremblay, Keith Orford, Gregory Verdine, Jonathan Hurov
Journal: Cancer Research (2023)

Abstract Genetic and epigenetic alterations in the Wnt signaling pathway leading to constitutive activation of the driver oncogene Β-catenin occur in at least 20% of all human cancers. We have developed conformationally hyperstabilized α-helical peptides (Helicons) that bind directly to Β-catenin with picomolar affinity and block its interaction with TCF transcription factors. We describe here the characterization of anti-tumor efficacy, pharmacodynamic biomarkers and mechanism of action using multiple in vivo patient-derived xenograft (PDX) models treated with Helicons. Helicon treatment leads to dose-dependent anti-tumor effects and durable regressions in PDX models from multiple indications with Wnt pathway activating mutations. Anti-tumor responses are seen in the presence of additional driver mutations, including KRAS and PIK3CA. RNA-sequencing and Gene Set Enrichment Analysis confirm Helicon treatment inhibits both Wnt/Β-catenin and MYC-regulated gene sets. Inhibiting Β-catenin-TCF interaction with Helicons represents a first-in-class therapeutic approach for the treatment of cancers resulting from aberrant transcriptional signaling via Β-catenin. Citation Format: YaGuang Si, Minjung Choi, Xinwei Han, Brian White, Ziyang Wu, Erica Visness, Pieter Beerepoot, Elizabeth Jaensch, Jessica Ramirez, Charles Ponthier, Xiaogang Han, Paula Ortet, Peicheng Du, Sorabh Agarwal, Mirek Lech, Aaron Fulgham, Sarah Cappucci, Zhi Li, John McGee, Lihua Yu, Martin Tremblay, Keith Orford, Gregory Verdine, Jonathan Hurov. Anti-tumor activity of Helicon inhibitors of Β-catenin-TCF interaction in patient-derived xenograft models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4972.